Intracellular pseudomonas aeruginosa exploits host through fatty acid handling

The National Institute of Allergy and Infectious Diseases, a component of the Department of Health and Human Services, awarded Vanderbilt University $100,228.00 on December 23, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) for a Project Grant to investigate how intracellular Pseudomonas aeruginosa exploits host fatty acid metabolism during urinary tract infections.

The funded research will identify mechanisms by which P. aeruginosa hijacks host fatty acid handling through the pseudomonal enzyme FADE2 and the host protein FABP3. P. aeruginosa is a WHO-listed priority pathogen frequently associated with complicated urinary tract infections that result in increased recurrence, hospitalization, and mortality. Preliminary RNA-sequencing data identified downregulation of FABP3 in murine bladders during infection; the project will test whether P. aeruginosa's FADE2 directly implicates this downregulation in mammalian models and determine how intracellular bacterial presence persists through chronic infection stages.

The period of performance runs through June 30, 2030, with work performed in Nashville, Tennessee.

Abstract

Urinary tract infections (UTIS) are among the most common bacterial infections, with rising numbers among men and women, increasing financial burden on medical systems. P. Aeruginosa is frequently associated with complicated urinary tract infections that result in increased recurrence, hospitalization, and mortality. Additionally, P. Aeruginosa remains a who-listed "priority pathogen" for its threat to human health. However, the pathogen is poorly studied in the bladder environment relative to its other infection niches. My long-term goal is to understand subversive mechanisms of pseudomonas that facilitate bacterial persistence and severity in UTIS. Our previous work demonstrated P. Aeruginosa can invade urothelial cells, establishing an intracellular presence in both murine bladder and in vitro. In preliminary rnaseq data presented here, I identified that the fatty acid binding protein, FABP3, is downregulated in murine bladders during infection by uropathogenic P. Aeruginosa. This downregulation persists over time into the chronic stages of UTI. Intriguingly, studies in C. Elegans previously reported that a pseudomonal acyl-COA dehydrogenase, FADE2, an enzyme that facilitates breakdown of fatty acids, alters host metabolism pathways and increases survival during chronic infection. FADE2 may, therefore, be directly implicated in downregulation of the host FABP3, but this potential connection has yet to be studied in mammalian models. The objective of this proposal is to identify how intracellular P. Aeruginosa exploits host fatty acid handling through changes in pseudomonal FADE2 and host FABP3. The central hypothesis is that P. Aeruginosa hijacks host fatty acid metabolism through the function of pseudomonal FADE2. The rationale is based on my identification of host fatty acid changes and literature supporting pseudomonal-induced host alterations by bacterial fatty acid genes. This work is innovative for its use of a novel human organoid model, providing strong translational impact, and will be the first investigation of either gene in the context of urinary tract infection. The hypothesis of this work will be tested through two specific aims: 1) I will define pseudomonal impact on fatty acid handling and inflammation by host FABP3 suppression and 2) I will determine the influence of pseudomonal FADE2 on host mitochondrial UPR and FABP3. The expected outcomes are to classify the host changes that result from pseudomonal suppression of FABP3 and establish whether a direct relationship exists between pseudomonal FADE2, host FABP3 and the changes in host fatty acid metabolism. The proposed research is significant to public health for its potential to identify a new mechanism for therapeutic targets against a pathogen associated with high antibiotic resistance.